A novel protein, MAPO1, that functions in apoptosis triggered by O6-methylguanine mispair in DNA

被引:8
作者
Komori, K. [2 ]
Takagi, Y. [3 ]
Sanada, M.
Lim, T-H [4 ]
Nakatsu, Y. [4 ]
Tsuzuki, T. [4 ]
Sekiguchi, M. [2 ,3 ]
Hidaka, M. [1 ,2 ,4 ]
机构
[1] Fukuoka Dent Coll, Dept Physiol Sci & Mol Biol, Sawara Ku, Fukuoka 8140193, Japan
[2] Biomol Engn Res Inst, Dept Mol Biol, Suita, Osaka, Japan
[3] Fukuoka Dent Coll, Frontier Res Ctr, Fukuoka 8140193, Japan
[4] Kyushu Univ, Fac Med Sci, Dept Med Biophys & Radiat Biol, Fukuoka 812, Japan
关键词
apoptosis; gene-trap mutagenesis; Mapo1; MGMT; O-6-methylguanine; EMBRYONIC STEM-CELLS; ALKYLATION-INDUCED APOPTOSIS; MISMATCH REPAIR; O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; ANTINEOPLASTIC DRUGS; ESCHERICHIA-COLI; INDUCE APOPTOSIS; KNOCKOUT MICE; MUTL-ALPHA; ATR KINASE;
D O I
10.1038/onc.2008.462
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
O-6-Methylguanine produced in DNA induces mutation due to its ambiguous base-pairing properties during DNA replication. To suppress such an outcome, organisms possess a mechanism to eliminate cells carrying O-6-methylguanine by inducing apoptosis that requires the function of mismatch repair proteins. To identify other factors involved in this apoptotic process, we performed retrovirus-mediated gene-trap mutagenesis and isolated a mutant that acquired resistance to a simple alkylating agent, N-methyl-N-nitrosourea (MNU). However, it was still sensitive to methyl methanesulfonate, 1-(4-amino-2methyl- 5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea, etoposide and ultraviolet irradiation. Moreover, the mutant exhibited an increased mutant frequency after exposure to MNU. The gene responsible was identified and designated Mapo1 (O-6-methylguanine- induced apoptosis 1). When the expression of the gene was inhibited by small interfering RNA, MNU-induced apoptosis was significantly suppressed. In the Mapo1-defective mutant cells treated with MNU, the mitochondrial membrane depolarization and caspase-3 activation were severely suppressed, although phosphorylation of p53, CHK1 and histone H2AX was observed. The orthologs of the Mapo1 gene are present in various organisms from nematode to humans. Both mouse and human MAPO1 proteins expressed in cells localize in the cytoplasm. We therefore propose that MAPO1 may play a role in the signaltransduction pathway of apoptosis induced by O-6-methyl-guanine-mispaired lesions.
引用
收藏
页码:1142 / 1150
页数:9
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